1. Field of the Invention
The present invention relates to a method for detecting a chelator content in a solid sample and, more particularly, to a direct solid sample analytical technology for determining a content and a uniformity thereof in a lyophilized kit of a sulfur-containing chelator with a stable complex capacity for radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188)
2. Description of Related Art
As well known to those skilled in the art, a sulfur-containing chelator, which is a soft chelator widely applied to chelating radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188), can complex stably with radiotechnetium and radiorhenium. Recently, a sulfur-containing radiopharmaceutical of radiotechnetium and radiorhenium comprises:
Tc-99m-ethyl cysteinate dimer (Tc-99m-ECD, a diagnostic drug for epilepsy), Tc-99m-mercaptoacetyltriglycine (Tc-99m-MAG3, a diagnostic drug for renal function), Tc-99m-dimercapto succinic acid (Tc-99m-DMSA, a diagnostic drug for renal cortex and pulmonary function), Tc-99m-N-NOET (a diagnostic drug for cardiac), Tc-99m-N-DBODC (a diagnostic drug for cardiac), Tropane derivatives (a contrast agent of dopamine transporters), Re-188 ECD/Lipiodol (a therapeutic drug of liver cancer) and an ethylenedicysteine-pharmaceutical adduct (capable of binding with various chelators and Tc-99m as disease constrasts) and the likes.
A general category of the sulfur-containing chelator, which can be complexed with radiotechnetium and radiorhenium, are shown in Table.1.
TABLE 1a general category of the sulfur-containing chelator whichcan be complexed with radiotechnetium and radiorhenium.Coordinating nucleus ofradiotechnetium and radiorheniumchelatorchelating structurePenta- and HexacoordinatedThiolatesScomplexes of oxo-Tc or  oxo-Re ([M═O]3+)  Aminothiolates   Dithiolates or dithioxalates   Tridentate dithiolates   Tridentate Schiff bases Diaminedithiolates Mercaptoacetamides MAG3 derivatives Thioalkyl-dithiol-thio Penta- and HexacoordinatedThioureaScomplexes of nitrido-Tc or nitrido-Re ([M≡N]2+)  Dithiocarbamate   Azomethines   Diaminedithiolates IsothiocyanateRN═C═S
As clinical use, a lyophilized kit comprising a chelator and a reductant is usually dissolved in a buffer solution, and then the chelating reaction (also known as complex reaction or radiolabeled reaction) is preceded by mixing radiotechnetium or radiorhenium. After producing a complex, a patient's intravenouse injection is performed.
Traditionally, most methods for measuring a content of a sulfur-containing chelator in a lyophilized kit are dissolving the sample, titrating then instrumental analyzing.
A first conventional method for measuring sulfur in liquid samples refers to Eschka method. The method is a standard method of the total sulfur content such as organic sulfur, inorganic sulfur and elemental sulfur, which is adopted by ISO and ASTM. However, the chemical pretreatment process of the method is too complicated and mainly applied to the measurement of the total sulfur content in coal, oil coke, and/or coke, and thereby the method is inappropriate for analyzing organic sulfur-containing chelators.
A second conventional method for measuring sulfur in liquid samples refers to using inductively coupled plasma atomic emission spectrometry (ICP-AES) and potentiometric to analyze sulfur content. The disadvantage of the method as described above is that the method is only used to analyze liquid samples, and thus many complicated chemical pretreatment processes before analyzing, including steps of decomposing, dissolving, purifying and the like, are a must. Because of rapid degradation after dissolving parts of the sulfur-containing chelator in the lyophilized kit such as ECD Vail A, some problems such as sample loss and contamination or the like, may be caused during processing. Accordingly, using instruments after dissolving samples such as high performance liquid chromatography (HPLC) or mass spectrometric analysis is not suitable for analyzing such samples. Further, the analytic method of the sulfur content is also related to the sulfur chemical conformation. For example, a third conventional method for measuring sulfur in liquid samples refers to Canfield et al. research, which a reduction method of chromium is used to analyze inorganic sulfur in sediments, shales and argillites, comprising pyrite elemental sulfur and volatile monosulfide. Nevertheless, the reduction method only has a higher specificity for reducing inorganic sulfur rather than reduces organic sulfur and sulfates, and thus fails to completely determine the real sulfur content of organic compounds.
Disadvantages for analyzing liquid samples may be known as described above, therefore, if solid samples may be directly analyzed, an analyte loss during dissolving samples may be avoided. Further, there may be many merits according to the undiluted samples, such as the increased analytic sensitivity, the decreased amount of requiring samples, the no requirement of corrosive and hazardous reagents, the frugal expenditure, the environmental protection and the faster analyzing rates. However, there are still some defects to directly analyze solid samples, including a difficult sample operation, especially during the process wherein samples are introduced into instruments, an arduous standard calibration due to the process of gasification and an analyte atomization which is related to forms and substrates of the analyte in solid samples, an unsatisfactory precision such as a range of 5˜25% of a relative standard deviation (RSD) for analyzing solid samples by solid sampling-graphite furnace atomic absorption spectrometry (SS-GFAAS) and Solid Sampling-Electrothermal Vaporization-Inductively Coupled Plasma-Mass Spectrometry (SS-ETV-ICP-MS), and other problems induced by introducing other substrates into instruments while directly analyzing. Additionally, the direct analysis of solid sample has a common range of 10˜20% of a relative standard deviation.
A first conventional method for measuring sulfur in solid samples refers to X-ray fluorescence spectroscopy, which is developed by Ne{hacek over (c)}emer et al for directly analyzing the sulfur content of solid powders in feed. However, the pattern resolution of the baseline separation may not be obtained by such a method, and thus quantitative analysis software is developed by them. Besides, a comprehensive standard uncertainty and an accuracy of such method are 12% and 2˜10% respectively, and the main error of such method derives from sampling uniformity of solid samples.
A second conventional method for measuring sulfur in solid samples refers to instrumental neutron activation analysis (INAA) which is developed by Ne{hacek over (c)}emer et al for directly analyzing the sulfur content of solid powders in feed. However, related equipments for neutron irradiating and radiation protecting are necessary for INAA, and 3000-5000 mg/kg of a lower detecting limit is unsatisfactory.
A third conventional method for measuring sulfur in solid samples refers to using an elemental analyzer. For example, a method which an elemental analyzer coupled with an isotope ratio mass spectrometer (Sieper et al.) was developed to simultaneously analyze the isotope ratio of elements including hydrogen, carbon, sulfur and nitrogen within twenty minutes. Besides, Carlo Erba elemental analyzer (Duz et al.) was applied to hydrogen, carbon, sulfur and nitrogen analysis in coal samples. Although using the elemental analyzer for solid samples has been known to Pharmaceutical industries and applied element content analysis to a single pharmaceutical, the method described above has never been used to directly analyze the content and uniformity thereof in the lyophilized kit of the sulfur-containing chelator with a stable complex capacity for radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188) until now.
Above all, a technology for directly analyzing solid samples is immediately needed, which may be easily operated, provided with high precision and applied for determining the content in the lyophilized kit of the sulfur-containing chelator with a stable complex capacity for radiotechnetium (Tc-99m) and radiorhenium (Re-186, Re-188), and thereby problems due to prior arts may be resolved.